This Competitive Revision Application will expand the scope of the specific aims, research design and methods of the current grant, funded to explore the osteoblast-intrinsic role of ?FosB proteins in bone formation. This expansion consists in adding an entirely new specific aim based on recently acquired data demonstrating a role for ?FosB and other antagonists to FosB and the AP1 transcriptional machinery in the central nervous system to regulate on the one hand bone formation and on the other hand energy expenditure and fat. We have recently partially explored the link between the bone and fat phenotypes of mice overexpressing ?FosB and published a few papers under the parent grant during the first funding cycle (Kveiborg et al., 2004;Sabatakos et al., 2000). However, two of our recent studies, one published last month (Rowe et al., 2009) and one being prepared for submission (see Appendix ASBMR Abstract, 2009), have generated some very exciting new data which in our view deserve further investigation and could lead to highly innovative findings with significant implications not only in osteoporosis but also in obesity and diabetes.Briefly, the first study demonstrated that ENO2-?FosB mice, which have high bone mass, exhibited an increase in energy expenditure leading to a decrease in adipocyte size and thereby fat mass. This was associated with decreased insulin levels, increased insulin sensitivity and better glucose tolerance. Since targeting ?FosB to adiposities failed to mimic the phenotype, we then turned to the central regulation of energy. In the second study, targeted expression of ?FosB or a constructed AP1 antagonist (Dominant Negative JunD) in the ventral portion of the hypothalamus recapitulated the entire phenotype of mice overexpressing ?FosB under the control of the ENO2 promoter, inducing an increase in energy expenditure, decreased physical activity, decreased fat mass and markedly increased bone formation and bone mass. The Specific Aim of this revision application is therefore to identify the neuronal circuit(s) affected by the hypothalamic expression of ?FosB (or engineered DNJunD), antagonists of the AP1 family of transcription factors, which lead to strong induction of bone formation with an increase in energy expenditure and a subsequent reduction in fat mass. The experiments proposed in this application could therefore lead to the identification of novel pathways regulating bone formation and novel targets for drug discovery, potentially allowing new approaches for anabolic therapeutic intervention in osteoporosis, but could also shed some light on the pathophysiology of Obesity and Diabetes. PUBLIC HEALTH RELEVANCE: We have found that a protein, when expressed in a region of the brain called hypothalamus, decreases insulin in the blood, decreases fat in the body and increases the density of bones in the skeleton. We will identify how it works in the brain, potentially allowing new approaches for therapeutic intervention in osteoporosis, but this work could open new avenues for the treatment of obesity and diabetes.